Biology is in the midst of intellectual upheaval. An era dominated by the systematic identification and characterization of parts-genes, proteins, cells-is rapidly yielding to one focused on complex interaction networks, the principles of their design, and their role in the context of organismal fitness and natural selection. The emerging field of Systems Biology breaks with the past not only in the types of questions it asks, but also in the diverse disciplines it draws heavily upon, including mathematics, computer science, engineering, and physics. Here we outline Phase II in the development of a training program in Mathematical, Computational and Systems Biology that was initiated under Phase I of the Howard Hughes Medical Institute/NIBIB Interfaces initiative. The program is a coordinated, interdisciplinary program designed to produce Ph.D.s that are prepared for careers in Systems Biology. Highlights of the program include an extensive didactic curriculum; a focus on critical thinking skills; an emphasis on collaboration and collaborative learning; close mentoring, opportunities to develop career skills; and active student involvement. The 38 program faculty members come from eleven different departments and five schools at the University of California, Irvine, and conduct research on diverse topics within Systems Biology. The program enjoys strong campus support and an administrative and intellectual home within an NIH-supported National Center for Systems Biology at UCI. RELEVANCE: Biological and biomedical research are increasingly focused on complex systems. By training the next generation of researchers in an interdisciplinary mode-blending biology with mathematics, computer science, engineering and physics, the proposed program will help future scientists and educators function effectively in this new research environment.